Tumor antigens are a group of proteins expressed by tumor cells. These antigens are divided into five categories according to their expression profile: (1) antigens specific for the patient, resulting from point mutations related to tumorigenesis, (2) tumor-specific antigens (TSA) expressed in many tumors and a few normal tissues devoid of conventional HLA molecules, (3) differentiation antigens which are expressed either during embryogenesis or in quite specific cell types, (4) antigens over expressed by tumors (such as survivin, gp75, PSA, HER-2, p53, and telomerase) and (5) viral antigens.
Human epidermal growth factor receptor-2 (also known as HER-2, HER-2/neu, c-erbB-2 or p185; hereinafter referred to as HER-2, HER-2 receptor, or HER-2 protein) is a 185 kDa protein that belongs to the epidermal growth factor receptor family. Sequences of human HER-2 and its orthologs are available from the NCBI web site: http://www.ncbi.nlm.nih.gov/, where the sequences are identified with the following RefSeq Identifiers: NP—004439.2 (human), XP—001090319.1 (rhesus), XP—001501155.1 (horse), NP—001003217.1 (dog), NP—001041628.1 (cat), NP—058699.2 (rat), and NP—001003817.1 (mouse). The amino acid sequence of the full length human HER-2 protein is provided in SEQ ID NO: 1. The DNA sequence encoding the amino acid sequence of the full length human HER-2 protein is provided in SEQ ID NO: 2. Human HER-2 protein consists of an extracellular domain (ECD) (amino acids 1-653), a transmembrane domain (TMD)(amino acids 654-675), and an intracellular domain (ICD)(amino acids 676-1255). The ECD includes a signal sequence that consists of amino acids 1-22. The ICD includes a tyrosine kinase domain (amino acids 720-787) and a carboxy terminal (C-terminal) domain (CTD)(amino acids 991-1255).
HER-2 protein has been found to be amplified and over expressed in several types of human adenocarcinomas, especially in tumors of the breast and the ovary. For example, HER-2 was found to be over expressed (3+) in 15-25% and moderately (1+) to highly (2+) expressed in 30-45% of the breast cancer patients. (See Perez E A, et al, HER2 testing in patients with Breast Cancer: Poor correlation between weak positivity by immunohistochemistry and gene amplification by fluorescence in situ hybridization. Mayo Clin. Proc. 2002; 77:148-154.) Therefore, for the purposes of this invention, such cancers are considered to be “cancers associated with HER-2.”
Several vaccine strategies targeting tumors that over express HER-2 using peptides, proteins, plasmid DNA, and viral vector approaches have been explored. For example, U.S. Pat. No. 7,348,018 mentions a peptide of the HER-2 ECD domain and its use for eliciting or enhancing an immune response. Published US patent application US2006/074038 refers to a HER-2 expressing plasmid construct encoding a truncated HER-2 gene that lacked the intracellular domain and the use of such a construct as a vaccine. Many of these strategies have seen little or no clinical responses mainly due to use of a single antigen and/or self antigens to induce immune responses that do not break immune tolerance or adequately activate dendritic cells (DCs) and expand cytotoxic T lymphocytes (CTLs).